Intestinal FXR deficiency uncouples steatosis protection from liver inflammation and fibrosis in MASH-diet fed mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE318026 | GEO | 2026/06/09
REPOSITORIES: GEO
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Project description:The bile-acid receptor FXR is known to be expressed in both intestine and liver, and FXR agonists are currently Under clinical evaluation for Metabolic Associated SteatoHepatitis (MASH) treatment. However, the specific question about activate or de-activate FXR specifically in the intestine in MASH is still unlear, protective results being available for both case.
2026-06-09 | GSE318468 | GEO
Project description:The inter-organ cross talk between liver and intestine has been focus of intense research. Key in this cross-talk are bile acids, which are secreted from the liver into the intestine and, via the enterohepatic circulation, reach back to the liver. Important new insights have been gained in the Farnesoid X receptor (Fxr)-mediated communication from intestine-to-liver in health and disease. However, liver-to-intestine communication and the role of bile acids and FXR in this cross talk remain elusive. Here, we analyse Fxr-mediated liver-to-gut communication, and its consequences in the colon. Mice in which Fxr was selectively ablated in intestine (Fxr-intKO), the liver (Fxr-livKO), or in the full body (Fxr-totKO) were engineered. The effects on colonic gene expression (RNA sequencing), on the microbiome (16S rRNA Gene Sequencing) and on mucus barrier were analyzed. Compared to Fxr-intKO and Fxr-totKO mice, more genes were differentially expressed in the colons of Fxr-livKO mice relative to control mice (731, 1824 and 3272 respectively), suggestive of a strong role of hepatic Fxr in liver-to-gut communication. The colons of Fxr-livKO showed increased expression of anti-microbial genes, such as Regenerating islet-derived 3 beta and gamma (Reg3β and Reg3γ), Toll-like receptors (Tlrs), inflammasome related genes and differential expression of genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Compared to control mice, Fxr-livKO mice have decreased levels of the predicted mucin degrading bacterium Turicibacter and a concomitant increase in the thickness of the inner sterile mucus layer. In conclusion, ablation of Fxr in the liver has a major effect on colonic gene expression, the gut microbiome and on the permeability of the mucus layer. This stresses the importance of the Fxr-mediated liver-to-gut signaling.
2021-09-29 | GSE163157 | GEO
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.
2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress
Project description:<p>Circadian disruption has emerged as a significant public health issue and is increasingly recognized as a contributor to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), though the underlying mechanisms remain poorly understood. In this study, we established a mouse model combining continuous light exposure and a western diet to investigate how circadian disruption exacerbates metabolic dysfunction-associated steatohepatitis (MASH). Our results demonstrated that circadian disturbance aggravated hepatic inflammation, lipid accumulation, and intestinal barrier impairment. Through integrated 16S rRNA sequencing and metabolomic analyses, we identified a marked reduction in Akkermansia muciniphila abundance and an elevation in CDCA-3S. Supplementation with A. muciniphila, taurine, or the FXR agonist obeticholic acid restored microbial and metabolic homeostasis, subsequently alleviating MASH pathology. Mechanistically, our data suggest these beneficial effects may involve the FXR–CYP7A1 signaling pathway. Our findings indicate that circadian disruption aggravates MASH potentially through reducing A. muciniphila abundance in a process associated with the FXR–CYP7A1–bile acid axis , and highlight the potential of microbial and metabolic interventions as novel therapeutic strategies for individuals with sleep-related circadian disorders.</p>
2026-02-05 | MTBLS13845 | MetaboLights
Project description:<p>Circadian disruption has emerged as a significant public health issue and is increasingly recognized as a contributor to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), though the underlying mechanisms remain poorly understood. In this study, we established a mouse model combining continuous light exposure and a western diet to investigate how circadian disruption exacerbates metabolic dysfunction-associated steatohepatitis (MASH). Our results demonstrated that circadian disturbance aggravated hepatic inflammation, lipid accumulation, and intestinal barrier impairment. Through integrated 16S rRNA sequencing and metabolomic analyses, we identified a marked reduction in Akkermansia muciniphila abundance and an elevation in CDCA-3S. Supplementation with A. muciniphila, taurine, or the FXR agonist obeticholic acid restored microbial and metabolic homeostasis, subsequently alleviating MASH pathology. Mechanistically, our data suggest these beneficial effects may involve the FXR–CYP7A1 signaling pathway. Our findings indicate that circadian disruption aggravates MASH potentially through reducing A. muciniphila abundance in a process associated with the FXR–CYP7A1–bile acid axis , and highlight the potential of microbial and metabolic interventions as novel therapeutic strategies for individuals with sleep-related circadian disorders.</p>
2026-02-05 | MTBLS13848 | MetaboLights
Project description:The Farnesoid-X-Receptor (FXR) is a nuclear receptor (NR) known to obligately heterodimerize with Retinoid-X-Receptor (RXR). FXR is expressed as four isoforms (α1-α4) that drive transcription from IR-1 (inverted repeat-1) DNA motifs. More recently, FXR isoforms α2/α4 were found to activate transcription predominantly from non-canonical ER-2 (everted repeat-2) DNA motifs, mediating most metabolic effects of general FXR activation.Here, we explored whether co-occupancy of FXR and RXR in the mouse liver has an influence on DNA motif binding preference. We found RXR acts as a molecular switch, promoting FXRα2 activation from IR-1 instead of ER-2 motifs. Our results showcase FXR as the first NR with RXR-dependent and independent modes of activation, highlighting a potential new layer of complexity for other RXR-heterodimerizing NRs.
2024-03-20 | GSE261901 | GEO
Project description:Farnesoid X receptor (FXR, also known as NR1H4) is crucial to nephroprotective in several kinds of kidney diseases, including obesity, diabetes, aging, acute kidney injury and chronic kidney disease. FXR plays a key role in maintaining cholesterol and bile acid levels and is highly expressed in the liver, intestine and kidneys. In kidney diseases, it is reported that FXR has anti-lipogenic, anti‐inflammatory, antifibrotic, and antioxidant functions. Here, using genomics analysis, we investigated whether FXR attenuates cisplatin-induced AKI through the regulation of ferroptosis. The increased blood urea nitrogen, serum creatinine and ferroptotic responses in cisplatin-induced AKI mice were attenuated by treatment with FXR agonist, GW4064, while those were exacerbated in FXR knockout mice. Using RNA-sequencing analysis, we found novel target genes for FXR associated with ferroptosis. FXR agonist treatment increases lipid and glutathione metabolic gene expression and decreases cell death genes expression. This study identifies transcriptional regulation of ferroptosis by FXR as a potential therapeutic target for cisplatin-induced AKI.
2022-07-06 | GSE193860 | GEO
Project description:The Farnesoid-X-Receptor (FXR) is a class II nuclear receptor (NR), a class that obligately heterodimerizes with the Retinoid-X-Receptor (RXR). FXR is expressed as 4 isoforms (α1-α4) activated by bile acids that drive transcription from response elements IR-1 (inverted repeat-1). We recently showed that FXR isoforms α2 and α4 bind to non-canonical response elements ER-2 (everted repeat-2), thereby increasing mitochondrial respiratory capacity and limiting de novo lipogenesis. Binding to ER-2 motifs in mouse liver organoids represented 89% of all FXR genome wide binding. However, mechanistic differences in FXR binding and activation from these two response elements remained unexplored. Using DNA pull down followed by mass-spectrometry, we show that RXR is not involved in FXR binding to ER-2 response elements. Instead, RXR inhibited FXR binding and activation from these elements in luciferase reporters. Genome wide, RXR-lacking FXR binding sites showed higher enrichment for ER-2 motifs in mouse liver. Pharmacological and mutational abrogation of FXR-RXR heterodimerization specifically retained ER-2 transactivation capacities in luciferase reporters and HepG2 cells. Transcriptome-wide, 25% of FXR targets were inhibited upon RXR overexpression, but specifically activated by a novel heterodimerization-deficient mutant FXRα2L434R. These genes were ER-2 responsive and were involved in lipid metabolism and ammonia detoxification. In conclusion, we discovered that RXR is not required and even inhibits binding of FXRα2 to ER-2. Thus, whereas FXR α1 and α3 seem to be genuine class II NR, FXRα2 and α4 are facultative class II at ER-2 motifs. This novel feature holds promise to exploit and tailor therapeutic responses to FXR agonism.
2024-11-12 | PXD047930 | Pride
Project description:Background & aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) ranges from simple steatosis (MAFL) to metabolic dysfunction-associated steatohepatitis (MASH). With the complex etiological factors associated with MAFLD, the molecular mechanism underlying the progression from steatosis to MASH has not been fully elucidated, resulting in a limited number of effective therapeutic interventions. Methods: We examined the profiling changes of MicroRNAs (miRNAs) in vivo and in vitro experiments and miR - 300 - 3p was identified as a crucial checkpoint in this process in the current experiments. The present studies were carried out to explore the role of miR - 300 - 3p in the advancement of MASH. Bioinformatic analysis, RNA - Sequencing, and dual - luciferase reporter assays were used to investigate the might target of miR - 300 - 3p. Results: We investigated the profiling changes of miRNA and identified miR - 300 - 3p is low expressed in mouse experiments and HepG2 cells. In vitro loss of function study revealed that suppression of miR - 300 - 3p in steatotic HepG2 cells could induce obvious inhibit cell autophagy, promote cell apoptosis, cause lipid accumulation, hepatic inflammation and injury, which are the primary characteristics within the pathology of MASH. STX17 was a predicted target gene of miR-300-3p through RNA-Sequencing, bioinformatic analysis and dual-luciferase reporter assays. Downregulation miR-300-3p was able to downregulate STX17 to promotes steatosis-to-MASH progression. In contrast, transduction of miR - 300 - 3p and over-STX17 inhibit steatosis-to_x0002_MASH progressionin. The results was inconsistent with canonical miRNA biology predicts, which indicated that the regulation of miR - 300 - 3p on STX17 might has context-dependent and involve indirect mechanism, feedback loop or multi-level control. Potentially clinically significant, the miR - 300 - 3p/STX17 regulatory axis has also been confirmed in human plasma. Expression level of miR - 300 - 3p and STX17 was reduced in plasma of MAFLD patients. Their expression levels were closely related to liver biochemical indicators and lipid profile indicators. Conclusion: Our research results highlight the function of the miR - 300 - 3p/ STX17 regulatory axis in the progression from steatosis to MASH. This suggests that either the supplementation of miR - 300 - 3p or STX17 may provide a promising therapeutic strategy for treating MASH in hepatocytes. The underlying mechanism through which miR - 300 - 3p regulates STX17 requires further investigation.
2026-05-20 | GSE328114 | GEO
Project description:The nuclear receptor, Farnesoid X Receptor (FXR, NR1H4), is a key transcriptional regulator of metabolism and a promising drug target for non-alcoholic fatty liver disease (NAFLD), a leading cause of liver failure and death. Protein coding genes regulated by FXR are known, but it remains unknown whether FXR mediates its function through regulating expression of long non-coding RNA (lncRNA) genes. Utilizing global RNA-seq and Gro-seq analyses, we identify an FXR-induced novel long non-coding RNA (lncRNA), termed FincoR.
2024-03-05 | GSE221986 | GEO